1. Field of the Invention
There is a great need for radiographic contrast media which are both non-toxic and economically produced, employing inexpensive and readily available intermediates and reagents. With increasing use of the larger doses demanded by new imaging methods, the incidence of untoward effects caused by ionic contrast media has become a serious concern. Newer, non-ionic radiographic contrast media are less toxic, but their high cost is a substantial deterrent to their generalized use and makes them a major factor in the expense of the diagnostic process. Development of low cost, non-ionic radiographic media has, therefore, become a particularly challenging area of synthetic organic chemistry.
Radiographic contrast media should be water soluble, non-toxic, and have a high iodine content. Most of these non-ionic radiographic contrast media are aromatic amides with one or more amino groups, having polyhydroxy, lower aliphatic alkyl and acyl subgroups bonded to nitrogen, with annular carboxamide and amino groups.
The final synthetic product contains a large number of functionalities in close spatial relationships. An expensive moiety, the triiodinated benzene ring, provides for a major portion of the weight of the product; once the aromatic ring has been iodinated, even small deviations from the theoretical yield can greatly affect the economics of the process. Also contributing to the cost are the water solubilizing functionalities, typically several hydroxyalkylamines, attached as amides. These amines include serinol, 1-amino-2,3-propanediol, N-methyl 1-amino-2,3-propanediol, and aminotetritols; and are all expensive.
In developing improved products it is essential that processes allow for substantial flexibility in the way solubilizing moieties are attached and/or generated on the aromatic ring. In addition, synthesis should provide for high yield, in all steps of the synthetic process.
2. Description of the Prior Art
German OS 2,658,300 describes the preparation of contrast media. See also U.S. Pat. No. 3,701,771 as illustrative of the preparation of contrast media. Also of interest are U.S. Pat. Nos. 4,001,323; 4,021,481 and 4,278,654, as well as UK Pat. Nos. 1,321,591 and 2,031,405; and Dutch application No. 79/05166.